Team 2a : T cell development and immune tolerance

Team 2a leaders: Dr. Carole Guillonneau & Dr. Matthieu Giraud
 

Research program

The primary focus of team 2a is the analysis of immune responses and induction of tolerance in transplantation, spanning both fundamental and translational research. Our work integrates advanced genetic engineering and stem cell approaches, which are essential for innovative discoveries. Notably, we have strengthened our translational impact through the creation of a start-up, with which we collaborate.

Our research obectives include:

1) CD8⁺ T Regulatory Cells (Tregs):

• We have a long-standing interest in CD8⁺ Tregs, investigating their phenotype, function, and TCR-peptide interactions.
• On the clinical side, we study their roles in pathological contexts and their potential as cellular therapies, including CAR-Tregs.
• We are initiating the world's first clinical trial using polyclonal CD8⁺ Tregs in kidney transplant patients, scheduled for 2025.

2) Thymus Self-Antigen Gene Regulation:

• We explore the regulation of self-antigen gene expression in the thymus, focusing on activating factors that synergize with or operate independently of AIRE.
• Our work also investigates the development and function of thymic epithelial cells (TECs) in rodents and humans.

3) Stem Cell Differentiation:

• We differentiate human embryonic stem (ES) and induced pluripotent stem (iPS) cells into CD34+ cells for humanizing immunodeficient rodent models.
• These cells are further differentiated into CD8+ Tregs as a source of therapeutic cells.
• We develop and advanced strategy to differentiate iPS cells into thymus organoids (containing medullary and cortical TECs) able to support full T cell development in vitro.

4) Tolerance-Inducing Immunotherapies:

• We develop novel immunotherapies targeting tolerance induction, including anti-CD45RC monoclonal antibodies (mAbs) and IL-34 cytokine-based strategies.

5) Epigenome Editing:

• We apply epigenome landscape profiling strategies such as single-cell ATAC-seq or ChIP-seq to identify and study the regions of the genome that have a potential for gene regulation activity and the role of epigenetic marks, particularly in thymic cells expressing self-antigens.

 

Platforms Managed by the Team

Rat Transgenesis TRIP Platform

• Led by Matthieu Giraud and Jérôme Jullien, TRIP specializes in generating genetically modified rats and other organisms.
• Services include the creation and distribution of rat models, genome editing research, and immunophenomic techniques.
• The platform is staffed by seven professionals (3 FTEs)

Molecular Biology/Vectorology Platform

• Directed by Laurent Tesson, this platform focuses on the development and optimization of molecular and vectorology techniques.
• It is supported by three technical staff members.

Rodent Facility and Microsurgery

• Led by Carole Guillonneau, the facility spans 400 m² and supports CR2TI research with mice and rat models.
• The team (3 technical staff) provides essential services, including basic animal care, microsurgical procedures (heart, kidney, and skin grafts), organ harvesting and immunomonitoring.

Grants

ANR Research Grants:

• EIGHT-TREG: CD8+ Tregs immune landscape in kidney transplantation and First-in-human cell therapy.
• SelfExpress: Identification of the regulators of self-antigen expression in the thymus and characterization of their role on the establishment of immunological tolerance.

National Grants:

• FRM Equipe: Allogeneic human CD8+ Tregs for cell therapy of immune-mediated disorder (StealthTregs)
• FRM Subvention Transplantation et Thérapie Cellulaire: Development of a universal cell therapy using allogeneic CD8+ Tregs.
• ARC TEC4TAG: Leveraging thymus epithelial cells for the discovery of public tumor-specific antigens.
• ARC PjA2: Development of a new CSF-1 and IL-34 blocker as cancer immunotherapy.
• Agence de la Biomédecine: Resolution of TCR-peptide complexes for donor-specific CD8+ Treg induction and graft monitoring.

International Grants:

• NORD (APS-1 Foundation) - TREGforAPECED

Industrial Collaborations:

• AbolerIS Pharma: use of an anti-CD45RC mAb in different pathologies and mechanisms of action.

Maturation fund for technology transfer:

• SATT Ouest Valorisation: Generation of regulatory T cells by thymus organoids for cell therapy.

Other support:

• Fondation Progreffe: Resolution of TCD-peptide complexes for donor-specific CD8+ Treg induction and graft monitoring.

 

Carole Guillonneau DR1 CNRS

Matthieu Giraud CR INSERM

Séverine Bézie  IR Nantes U

Ignacio Anegon Emerite INSERM

Diego CANTAROVICH - PH

Ghenima AHMIL-BOITEAU - IE
Lisa DUGAST - IE
Romain HUMEAU - IE
Juliette LASSELIN - IE
Antoine LE BOZEC - Ing.
Marie MASSODA - IE
Séverine MENORET - IR1
Laure-Hélène OUISSE - IH
Séverine REMY - IR
Sonia SALLE - IE
Laurent TESSON - IHP
Claire USAL - IE
Axel YOU - IE

Manon D'ARCO
Emma LEGUEDEY
Charleen PLAISSE
Sümeyye YAYILKAN